AEGiS-14IAC: HIV envelope-induced cell death requires coreceptor expression and gp41 function.

14th International AIDS Conference

Barcelona, Spain - July 7-12, 2002

HIV envelope-induced cell death requires coreceptor expression and gp41 function.

Int Conf AIDS 2002 Jul 7-12; 14:(abstract no. A10012)

Blanco J, Barretina J, Clotet B, Este JA
Fundacio irsiCaixa, Hosp. Germans Trias i Pujol, 08916 BADALONA, Spain

BACKGROUND: Cell surface HIV envelope (Env) mediates the death of single CD4 T cells by a gp41-dependent mechanism that involves lipid but not cytoplasm mixing between Env+ cells and CD4+ cells. However, the difference between X4 and R5 Env and the role of cellular receptors on such effect has not been fully characterized.

METHODS: We have studied the death of primary CD4 T cells and different cell lines expressing or not CD4, CXCR4 and CCR5, after coculture with cells expressing HIV Env from different X4 and R5 isolates. Cell death was evaluated by changes in nuclear or cellular morphology and mitochondrial function.

RESULTS: Primary peripheral CD4 T cells die after coculture with cells expressing X4 Env (IIIB, NL4-3, AOM-SI). Cell death increased from 9±2 % to 45±3 %, after 24 hours of culture. Little effect (an increase from 9±2 to 12±3% in cell death) was observed when primary CD4 T cells were cocultured with cells expressing an R5 HIV Env (BaL), most probably due to the low expression of CCR5 in primary T cells. We observed similar levels of gp41-dependent single cell death in cocultures of A3.F7 (CD4+/CXCR4+/CCR5+) cells with cells expressing X4 (NL4-3) or R5 (BaL) Env. A2.01 cells (CD4-/CXCR4+/CCR5+) were resistant to X4 and R5 Env induced apoptosis and the parental cell line CEM (CD4+/CXCR4+/CCR5-) was only sensitive to X4 but resistant to R5 Env-induced apoptosis. In all cultures, single cell death and syncytium formation were inhibited by drugs targeting gp41 function (such as C34), confirming that the apoptotic activity of both X4 and R5 Env required not only CD4 and coreceptor engagement but also gp41 function.

CONCLUSION: Our data show that CD4 expression is not sufficient to render a cell sensitive to cell-surface Env-induced apoptosis. X4 and R5 Env induce cell death by a gp41 dependent mechanism that requires the interaction of gp120 with CD4 and the appropriate coreceptor.

Keywords: AEGIS, Antigens, CD4, HIV Infections, Cell Death, CD4-Positive T-Lymphocytes, HIV Seropositivity, Apoptosis, T-Lymphocytes, Cell Line, physiology, immunology

020707
A10012